Radiotherapy plays an important role in the management of a variety of malignancies. However, radiation pneumonitis, an acute or subacute lung injury occuring 6-24 weeks following radiotherapy, is the dominant dose-limiting normal tissue effect of thoracic radiotherapy and prediction of patients at risk, prevention and effective therapy is an important goal in improving outcomes of affected patients. Although the exact molecular etiology is controversial a potentially important cellular target in radiation-induced lung injury (RILI) Is the lung endothelium, a functionally dynamic tissue that forms a semi-permeable barrier that regulates influx of macromolecules and fluid between the vascular compartment and the lung interstitium. Disruption of endothelial cell (EC) barrier integrity is a cardinal feature of pulmonary inflammation in general and radiation pneumonitis in particular, resulting in increased permeability and alveolar flooding followed by physiological derangements including impaired gas exchange. We hypothesize that stabilization or enhanced restoration of lung EC barrier integrity is a critical step in preventing or reducing acute RILI. As we have previously demonstrated the potent endothelial barrier-protective effects of sphingosine 1-phosphjate (S1P), a bioactive phospholipid, both in vitro and in animal models of inflammatory lung injury we now hypothesize that sphingolipids may serve as a highly novel and effective therapy for RILI. The mechanisms of SIP-mediated EC barrier function involve ligation of specific SIP receptor subtypes (SI P I , S1P2, and S1P3) but the relevance of these effects clinically are unkown. We will examine the role of S1P receptor ligation in modulating RILI in a relevant murine model. We will then extend these findings to investigate novel RILI therapies, including SIP analogues and simvastatin, an HMG CoA-reductase inhibitor which we have confirmed is both directly EC barrier-protective and induces the marked upregulation of SI PI. Finally, mouse and human RILI samples will be used to identify novel SIP-related biomarkers and genomic markers. Collectively, these studies will confirm the therapeutic role of sphingolipids in RILI and will potentially lead to novel applications of our understanding of sphingolipid biology in the management of patients with RILI.